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Immune surveillance against cancer

Early stage tumor suppression through immune surveillance: HZI researchers describe a new mechanism

Liver cancer (hepatocellular carcinoma) cell carcinoma is one of the most common malignancies worldwide. In the majority of cases hepatocellular carcinoma develops after chronic liver damage due to chronic Hepatitis B or C virus infections. Researchers at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and Hanover Medical School have now revealed how an intact immune system is able to recognize and eliminate premalignant liver cells at an early stage. Cells which are at a high risk for malignant transformation – e.g. as a result of chemical stress or radiation – often exit from their normal life cycle and enter a state of arrest, designated as “senescence”. Together with co-workers from other research institutions the HZI scientists discovered that such senescent cells make themselves visible for the immune system, e.g. by secreting factors which can attract immune cells. As a result, senescent cells are continuously cleared by the immune system, a mechanism which was designated as “senescence surveillance”. The researchers found that a continuous immune surveillance of senescent hepatocytes is important to suppress the development of liver cancer and the y propose that a mechanism, similar to the one shown for the liver, may play a key role in tumor suppression in other organs as well. The results of the study have now been published in an advance online release by the renowned scientific journal “Nature”.

At the end of their life cycle or if their genetic information gets damaged, cells either undergo a programme of controlled cell death or, alternatively, enter a kind of “hibernation”, the so-called cellular senescence program. This arrest prevents defective cells from uncontrolled proliferation and thus avoids the formation of tumors. Professor Lars Zender, head of the HZI research group Chronic Infections and Cancer and his team were able to demonstrate that the immune system plays a crucial role in the continuous surveillance of these resting cells. “By this means it prevented that the damaged cells can acquire further alterations which may result in the development of aggressive tumors”, explains Lars Zender.

To analyze how the senescence program and the immune system interact to prevent tumor development Lars Zender and his team used a genetic method to induce the senescence programme in liver cells of laboratory mice. “It was impressive to see, how efficient the immune system recognizes and eliminates modified cells”, says Zender. After a few weeks the modified, senescent cells were eliminated.

In immunodeficient mice that so called T-helper cells, researchers were able to observe that senescent liver cells were not cleared but rather progressed into liver carcinomas. “This clearly shows how important the surveillance of senescent cells is – a task carried out by the immune system, and specifically coordinated by T-helper cells”, says Zender.

This newly identified mechanism may also help to explain why HIV-positive patients have an increased risk of developing liver cancer. To investigate this phenomenon, researchers determined the number of senescent cells in the livers of patients with chronic Hepatitis C virus infection that were also HIV-positive. The results were compared to the numbers of senescent cells in livers of Hepatitis C virus infected patients without HIV infection. “As expected, in the group of Hepatitis C/HIV coinfected patients the number of senescent cells was strongly increased”, says Zender. “In HIV patients, the activity of T-helper cells is impaired and, as a consequence, - senescent liver cells probably cannot be eliminated effectively.”

The authors of the study believe that the newly discovered mechanism will enable new prevention- and therapeutic strategies to against cancer.